An ophthalmic preparation containing an immunosuppressant may contain cyclosporine, sirolimus, tacrolimus, or a derivative thereof. Among these, cyclosporine, which is known to be effective in treatment of dry eye syndrome, includes cyclosporine A, cyclosporine B, cyclosporine C and cyclosporine D, but cyclosporine A and derivatives thereof are the most widely researched.
However, it is generally known that since cyclosporine has a very low water solubility of approximately 20 to 30 μg/ml, it is difficult to prepare a drug compound containing cyclosporine that is dissolved in an aqueous medium, and such a drug compound is the commercially available Restasis® (cyclosporine ophthalmic emulsion 0.05%).
An emulsion refers to a liquid-liquid dispersion system in which at least one liquid is dispersed in another liquid with which it is immiscible, and the emulsion generally has a size distribution ranging from 0.1 to several tens of micrometers. Microemulsions are thermodynamically unstable, and eventually separate through various routes, for example, flocculation, sedimentation, creaming, Ostwald ripening, coalescence, etc. In this connection, when sizes of dispersion-phase emulsion particles are reduced to a nano scale, according to the Brown's movement between the particles, in a kinetic aspect, stability of an emulsion can be significantly enhanced, and the commercially available Restasis® is a nanoemulsion prepared by reducing a particle size of a dispersed phase to a nano scale.
Meanwhile, in processes of preparing known nanoemlusions including Restasis®, a high pressure homogenizer that applies high physical power to an emulsion, or a high speed stirring or shearing machine such as a microfluidizer is used. The preparation method requires large preparation equipment, consumes high costs, and applies high energy to an emulsion, so that a temperature is highly increased during emulsification, and it is difficult to apply to a component vulnerable to heat. In addition, Restasis® prepared by the above-described method has non-uniform particle size in the emulsion, and thus more flocculation occurs and creaming rapidly progresses, which results in a problem of long-term storage. In addition, when the high pressure homogenizer is used, due to instability of phospholipids at a high temperature (e.g., oil separation, creaming, etc.), smell change or high temperature stability is reduced, and particularly, since a distribution of particles of a dispersed phase is relatively wider, it is difficult to ensure uniform product quality in every preparation lot.
In relation to the above-described problem, the inventors developed a technique of preparing a nanoemulsion ophthalmic composition having an average particle size of 200 nm or less only by simple mixing and stirring oil and an aqueous component in the preparation of the emulsion (Korean Patent No. 1008189). However, when the patent composition is actually applied to eyes, the eyes become very irritated.